2-amino-3,4-dihydroquinazolines



United States l atent O 3,496,179 2-AMINO-3,4-DIHYDROQUINAZOLINES Hans-Jurgen E. Hess, Groton, Conn., assignor to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Oct. 11, 1967, Ser. No. 674,653 Int. Cl. C07d 51/48; A61k 27/00 US. Cl. 260-2564 3 Claims ABSTRACT OF THE DISCLOSURE Substituted 2-amino-3,4-dihydroquinazolines and their pharmaceutically-acceptable acid addition salts. Compounds manifest anti-hypertensive response with minimal adverse effects upon administration to afflicted subjects.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The compounds of this invention are those of the following formulae:

and the acid addition salts, particularly the pharmaceutically acceptable acid additon salts, thereof.

In these compounds X and Y may be hydrogen, hydroxy, halogen, CF alkyl or alkoxy with up to 4 carbon atoms in the alkyl and alkoxy groups and X and Y may be the same or different. When taken together, X and Y may be benzo, methylenedioxy or ethylenedioxy. R and R may also be the same or different and may be hydrogen, alkyl having up to 6 carbon atoms, aryl hydrocarbon having up to 12 carbon atoms, aralkyl hydrocarbon having up to 3 carbon atoms in the alkyl moiety and up to 7 carbon atoms in the aryl moiety and wherein the carbon atom bearing the aryl substitutent may be an optically active site, alkenyl having up to 4 carbon atoms, or dialkylaminoalkyl having from 2 to 4 carbon atoms in the nitrogen-bridging alkyl moiety 3,496,179 Patented Feb. 17, 1970 of the dialkylaminoalkyl substituent and up to 3 carbon atoms in the terminal alkyl moieties of the dialkylaminoalkyl substituent. With reference to the dialkylaminoalkyl substitutent, the nitrogen-bridging alkyl moiety is the alkyl group which is bonded to the nitrogen atom at the 2-position of the quinazoline moiety and also bonded to the nitrogen atom which is part of the dialkylaminoalkyl substituent; the terminal alkyl moieties are the alkyl groups which are bonded only to the nitrogen atom which is part of the dialkylaminoalkyl substituent. When R or R is aryl or aralkyl, the aryl moiety may be substituted with halogen, CE, or alkoxy having up to 4 carbon atoms. R and R taken together, may be cycloalkyl having from 3 to 7 carbon atoms.

R may be hydrogen, alkyl having up to 4 carbon atoms, aryl hydrocarbon having up to 12 carbon atoms or aralkyl hydrocarbon having up to 3 carbon atoms in the alkyl moiety and up to 7 carbon atoms in the aryl moiety. Where R is aryl or aralkyl, the aryl moiety may be substituted with halogen, CF or alkoxy having up to 4 carbon atoms. R, may be morpholino, N-alkylpiperazino with up to 6 carbon atoms in the alkyl group, N-alkenyl-piperazino with up to 4 carbon atoms in the alkenyl group, or N-phenyl-piperazino where the phenyl group may be substituted with halogen, CF alkyl having up to 6 carbon atoms or alkoxy having up to 6 carbon atoms.

These compounds are effective in inducing hypotensive action in subjects to which an effective amount of the compound is administered. Particularly preferred compounds are 2-diethylamino-3,4-dihydro-6,7-dimethoxyquinazoline and 2-dimethylamino-3,4 dihydro-6,7-dimethoxyquinazoline. Particularly preferred acid addition salts are the hydrochloride salts of these compounds.

The compounds may be administered to afflicted sub jects orally or parenterally in suitable dosage forms.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to the compounds of Formulae I and II, as presented above, with the substituents as set out above.

The compounds of this invention, where R is hydrogen, may be produced from the corresponding 3,4-dihydroquinazoline-4-ones. In this procedure the 4-position of the quinazoline is first chlorinated, using phosphorus oxychloride. The 3,4-dihydroquinazoline is then produced by reacting the corresponding 4-chloro compound with hydrogen in the presence of a palladium catalyst supported on carbon.

The chlorination reaction may be performed by refluxing the appropriate quinazolinone hydrochloride in phosphorus oxychloride for a period of from 0.5 to 48 hours. The reduction of the 4-chloro compound may be performed at atmospheric or elevated pressures over a period of from 0.5 hour to 72 hours at a temperature from 20 C. to C.

The initial 2-amino-3,4-dihydroquinazoline-4-ones are produced by reacting the corresponding 2-halo-3,4-dihydroquinazoline-4-ones with the appropriate amine base, viz., R NR where R and R are as previously defined. The 2-halo-3,4-dihydroquinazoline-4-ones are obtained by treating the corresponding 2,4-dihaloquinazolines with a strong base compound such as an alkali metal hydroxide in an aqueous reaction medium which may also contain an organic solvent. For example, 2,4-dichloro-6,7-dimethoxyquinazoline has been prepared according to the procedure described by F. H. S. Curd et al. in the Journal of the Chemical Society (London), 1948, p. 1759. This procedure is also applicable to other starting 2,4-dihaloquinazolines.

The compounds in which R is other than hydrogen are prepared as follows. First, an ester of the anthranilic acid is cyclized by reaction with RgNCO (where R is defined above) in the presence of pyridine followed by treatment with sodium hydroxide. The resultant 3-substituted-2,4(1H, 3 H)-quinazolinedione is then refluxed in phosphorus oxychloride to chlorinate the 2-position. The resultant 2-chloro-3-substituted-4-quinazolinone is then reacted with R NR or R, (where R R and R,; are defined above) to form the 2-amino-3-substituted-4(3H)- quinazolinone. This latter compound is then reacted with phosphorus pentasulfide to form the corresponding quinazolinethione. The 4-position of the quinazolinethione is reduced by refluxing the compound in methanol in the presence of Raney nickel catalyst, whereby the corresponding 2-amino-3-substituted-3,4-dihydroquinazoline is formed.

Compounds in which the 5-, 6-, 7-, or 8-positions are substituted with hydroxy are obtained by O-dealkylation of the corresponding alkoxy derivatives with 48% aqueous hydrobromic acid.

The substituents at the 5-, 6-, 7- or 8-positions of the final dihydroquinazoline product are controlled by the nature of the original anthranilic acid ester; the substituent at the 3-position is controlled by the isocyanate which is used to cyclize the anthranilic acid ester; the Z-amino substituent is controlled by the nature of the amine which is reacted at the chlorinated Z-position.

Typical quinazolines, substituted at one or more of the 5-, 6-, 7- or 8- positions, which are obtainable from the various substituted o-aminobenzoic acid esters by the cyclization process outlined above are shown in Table I with their starting compounds.

TABLE I.-SUBSTITUTED QUINAZOLINES Starting compound: Substituents Methyl 4-methoxyanthranilate 7-methoxy. Methyl S-methoxyanthranilate 6-methoxy. Methyl 6-chloroanthranilate S-chloro. Methyl 4,5 diethyleneoxyanthranilate 6,7 ethylenedioxy. Methyl 3-methylanthranilate B-methyl. Methyl 6-aminoveratrate 6,7-dimethoxy.

Variations of these procedures which also may be used to prepare the compounds of this invention from other similar compounds and by other methods will be obvious to those skilled in the art.

For example, the appropriate toluene-a,2-diamines may be cyclized to 3,4-dihydro-2(1H)-quinazolinones which may then be chlorinated with phosphorus oxychloride. The 2-cl1lor0 derivative is then reacted with an appropriate amine to yield the desired products. A typical reaction scheme is as follows:

The well-known procedures for preparing salts of basic compounds are also applicable to the preparation of the compounds of this invention. Such salts may be formed with both pharmaceutically-acceptable and pharmaceutically-unacceptable acids. By "pharmaceutically-acceptable is meant those salt-forming acids which do not substantially increase the toxicity of the basic compound. The preferred salts, which are of particular value in therapy, are the acid addition salts. These include salts of mineral acids such as hydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, maleic, methylsulfonic, ethanesulfonic, benzenesulfonic, para-toluene-sulfonic and gluconic as Well as other suitable acids.

The pharmaceutically-unacceptable acid addition salts, while not useful for therapy, are valuable for use in the isolation and purification of these newly discovered compounds. Furthermore, they are useful for the preparation of the therapeutically valuable pharmaceutically-acceptable salts. Of this group, the more common salts include those formed with hydrofluoric and perchloric acids. Hydrofluoride salts are particularly useful for the preparation of the pharmaceutically-acceptable salts.

The compounds of this invention may be administered to hypertensive subjects in order to alleviate this condition. The compounds of this invention may be administered alone or in combinations with pharmaceuticallyacceptable carriers. The proportion of the active ingredient to carrier is determined by the solubility and chemical nature of the therapeutic compounds, the chosen route of administration and the needs of the standard pharmaceutical practice. For example, where these compounds are administered in tablet form, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate may be used. Various disintegrants such as starch, alginic acids, and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, may also be used in producing tablets for the oral administration of these compounds. For oral administration in capsule form, lactose and high molecular weight polyethylene glycols are preferred materials for use as pharmaceutically-acceptable carriers. Where aqueous suspensions are to be used for oral administration, the compounds of this invention may be combined with emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerine and their combinations may be employed as well as other materials. Solutions of the compounds of this invention in combination with other solutes such as glucose or saline may be used where the compounds are to be administered parenterally. Such aqueous solutions should be suitably buttered, if necessary, to render them isotonic.

The dosage required to reduce the blood pressure of the hypertensive subjects will be determined by the nature and the extent of the hypertension. Generally, small dosages will be administered initially with gradual increase in dosage until the optimal dosage level is determined for the particular subject under treatment. It will generally be found that when the composition is administered orally, larger quantities of the active ingredient will be required in order to produce the same level of blood pressure reduction as would be produced by the smaller quantity of active compound which is administered parenterally. In general, dosages will be in the range from about 0.1 to 40 milligrams of active ingredient per kilogram of body weight of subject, administered in single or multiple dosage units. Dosages at this level will effectively reduce blood pressure in hypertensive subjects. Tablets containing 0.1 to 50 milligrams of active ingredient are found to be particularly useful.

The therapeutic effects of the compounds of this inven- I tion have been evaluated in dogs. It was found that the compounds manifested therapeutic action over extended periods of time and were easily absorbed into the treated subjects upon oral administration. The effectiveness of the compounds of this invention as therapeutic agents was measured with respect to known hypotensive agents.

It will be understood that various changes in the details, materials and steps which have been herein described and illustrated in order to explain the nature of this invention may be made by those skilled in the art within the principle and scope of the invention as expressed in the appended claims.

The following examples are given by way of illustration only and are not to be construed as limiting the scope of this invention in any way.

EXAMPLE I Preparation of 2-diethylamino-3,4-dihydro-6,7-

dimethoxyquinazoline hydrochloride Part APreparation of 2-diethylamino-4-chloro-6,7-dimethoxyquinazoline.A mixture of 10 g. of 2-diethylamino-6,7-dimethoxy-4 3H quinazolinone hydrochloride in 50 ml. of phosphorus oxychloride was refluxed for 2 hours. The liquids were evaporated to give 2-diethylamino-4-chloro-6,7-dimethoxyquinazoline hydrochloride as a crystalline residue, M.P. 175186. This material was dissolved in dilute sodium bicarbonate solution and the solution extracted several times with chloroform. The combined chloroform extracts were dried with sodium sulfate and the solvent was evaporated to furnish 7.6 g. (82%) of Z-diethylamino-4-chloro-6,7-dimethoxyquinazoline.

Analysis.-Calcd. for C H O N Cl: C, 56.86; H, 6.13; N, 14.21. Found: C, 56.81; H, 6.08; N, 13.97.

Part BPreparation of Z-diethylamino-3,4-dihydro-6,7- dimethoxyquinazoline hydrochloride. To a solution of 34.1 g. of 2-diethylamino-4-chloro-6,7-dimethoxyquinazoline hydrochloride in 500 ml. of ethanol was added 1.5 g. of 10% palladium on carbon catalyst and the mixture was hydrogenated at atmospheric pressure. When two moles of hydrogen were absorbed, the catalyst was filtered and the filtrate was concentrated to dryness. Recrystallization of the residue from methanol ethylacetate gave 184 g. (77%) of 2-diethylamino-3,4-dihydro-6,7- dimethoxyquinazoline hydrochloride.

Analysis.-Calcd. for C H N O HCl: C, 56.09; H, 7.04; N, 14.01; Cl, 11.82. Found: C, 55.88; H, 7.35; N, 13.86; Cl. 11.66.

EXAMPLE II Preparation of 2-dimethylamino-3,4-dihydro-6,7- dimethoxyquinazoline hydrochloride Part APreparation of 2-dimethylamino-4-chloro-6,7- dimethoxyquinazoline.The procedures of Part A of Example I were carried out using 2-dimethylamino-6,7- dimethoxy-4(3H)quinazolinone as a starting reagent. The resultant 2 dimethylamino-4-chloro-6,7-dimethoxyquinazoline was obtained in a yield of 90% and manifested a melting point of 175 to 180 C.

Part B-Preparation of 2-dimethylamino-3,4-dihydro- 6,7-dimethoxyquinazoline hydrochloride-The procedures of Part B of Example I were carried out using the 2-dimethylamino-4-chloro-6,7-dimethoxyquinazoline produced by the procedure set out in Part A, above. The resultant 2-dimethylamino 3,4 dihydro-6,7-dimethoxyquinazoline was produced in a yield of 43% and manifested a melting point of 301302 C.

EXAMPLE III Preparation of Z-diethylamino-3-methyl-6,7-dimethoxy- 3,4-dihydroquinazoline Part APreparation of 3-methyl-6,7-dimethoxy-2,4- (1H,3H)-quinazolinedione.To 25 g. of methyl isocyamate in 100 ml. of pyridine at C. was added a cold solution of 27 g. (0.28 mole) of methyl 6-aminoveratrate in 150 ml. of pyridine. The resulting solution was first stirred at 0 C. for 30 minutes, then kept at room temperature for 1 hour, and subsequently concentrated to dryness. The crystalline residue was dissolved in 630 ml. of methanolic 1 N sodium hydroxide solution (4:1, methanol-water) and refluxed for 2 hours. After evaporation of the solvent, the crystalline cake was dissolved in water, the solution acidified with glacial acetic acid, and the solids were filtered to give 32 g. material of M.P. 293297 C. This was recrystallized from dimethylformamide-water to afford 29.1 g. (93%) of the desired product, M.P. 296-298 C.

Analysis.Calcd. for C H N O C, 55.93; H, 5.12; N, 11.86. Found: C, 56.14; H, 5.08; N, 12.08.

Part EPreparation of 2-chloro-3-methyl-6,7-dimethoxy-4-quinazolinone.A mixture of 3-methyl-6,7-dimethoxy-2,4( lH,3H)quinazolinedi0ne and 65 ml. of phosphorus oxychloride was refluxed for 18 hours. The excess phosphorus oxychloride was then removed in vacuo, the resulting crystalline residue was triturated with 500 ml. of ice water, and the solids were collected and dried to yield 9.42 g. of crude 2-chloro-3-methyl-6,7-dimethoxy- 4(3H)-quinazolinone, M.P. 196-214 C. This material was used in Part C (below) without purification.

Part CPreparation of 2-diethylamino-3-methyl-6,7- dimethoxy-4(3H)-quinazolinone.A slurry of 2-chloro- 3-methyl-6,7-dimethoxy-4(3H)-quinazolinone (8 g.) in ml. of ethanol and 30 ml. of diethylamine was transferred to a pressure bottle and heated to 130 C. After 3 hours at that temperature, the solution was cooled, concentrated, and the residue was triturated with ml. of water. Filtration of the solids afforded 6.8 g. of crystalline material which was recrystallized from hot ethyl acetate to afford 3.9 g. (43%) of the desired product, M.P. 126-129 C. Two more recrystallizations from ethyl acetate-isopropyl ether and methanol-water, respectively, gave the analytical sample M.P. 13l133 C.; A 247, 289, 320 m (e 37,400; 12,800; 4,870); p.m.r. absorption at 2.421- (singlet, assigned to proton in position 5), 3.021- (singlet, proton in position 8), 6.07 (singlet, 6 protons of 6,7-OCH 6.581- (singlet, 3 protons of 3-CH 6.757 (quartet, 4 methylene protons of -N(CH CH 8.837 (triplet, 6 methyl protons of N(CH CH Analysis.Calcd. for C H N O C, 61.84; H, 7.21; N, 14.42. Found: C, 61.81; H, 7.12; N, 14.74.

Part DPreparation of 2diethylamino-3-methyl-6,7- dimethoxy-4(3H)-quinazolinethione.To 10 g. of 2-diethylamino-3-methyl-6,7-dimethoxy 4(3H)quinazolinone in 200 ml. of pyridine was added 30 g. of phosphorus pentasulfide and the mixture was refluxed with continuous stirring for 5 hours. The solvent was removed under reduced pressure and the residue was triturated with hot water. The remaining solid material was filtered to give the desired product.

Part EPreparation of Z-diethylamino-3-methyl-6,7- dimethoxy-3,4-dihydroquinazoline.-To a solution of 8 g. of 2 diethylamino-3-methyl-6,7-dimethoxy-4(3H)-quinazolinethione in 300 ml. of methanol was added 32 g. of Raney nickel catalyst and the mixture was heated at reflux temperature for 3 hours. During this time an additional 32 g. of catalyst was added in portions. The suspension was cooled and the catalyst filtered and washed well with methanol. The filtrate, when concentrated to a small volume, precipitated the desired product as crystals.

EXAMPLE IV Preparation of 2-diethylamino-3-(o-tolyl)-6,7- dimethoxy-3,4-dihydroquinazoline Part APreparation of 3-o-tolyl-6,7-dimethoxy-2,4 (1H,3H)-quinazolinedione.-To 108 g. of o-tolyl-isocyanate in 200 m1. of pyridine at C. was added an ice cold solution of methyl G-aminoveratrate (50 g.) in 400 ml. of pyridine. After stirring at 0 C. for approximately 45 minutes, a heavy precipitate formed. An additional amount of o-tolylisocyanate (92 g.) was added, and stirring was continued for 3 more hours at 0 C. The mixture was then stirred for 1 hour at room temperature and concentrated to dryness in vacuo. The resulting residue was dissolved in 1 liter of 1 N methanolic sodium hydroxide solution (4:1, methanol-water) and refluxed for 2 hours. Evaporation of the solvent gave solids which were dissolved in hot water. The solution was filtered, cooled, and acidified with glacial acetic acid. The precipitate that formed Was filtered and dried, furnishing 74.5 g. of crystalline material which was recrystallized from dimethylfonnamide-water to give 69.5 g. (94%) of the desired product, M.P. 281-283 C.

AnalySis.Calcd. for C17H16N204: C, H, N, 8.97. Found: C, 65.26; H, 503; N, 7.03.

Part BPreparation of 2-chloro-3-(o-toly1)-6,7-dimethoXy-4(3I-I)-quinazolin-one.-The quinazolinedione produced in Part A g.) was refluxed in 350 m1. of phosphorus oxychloride for hours. Removal of the phosphorus oxychloride furnished a crystalline residue which was quenched with 1 liter of Water, filtered, and dried to aiford 25 g. of crude 2-chloro-3-(o-tolyl)-6,7-dimthoxy- 4(3H)-quinazolinone, M.P. 203-240 C., which was used in the next step without further purification.

Part CPreparation of 2-diethylarnino-3-(o-tolyl)-6,7- dimethoxy-4(3H)-quinazolinone.-The chloro derivative Part D-Preparation of 2-diethylamino-3-(o-tolyl)- 6,7-dimethoxy-4(3H)-quinazolinethi0ne.The Z-diethylamino 3 (o tolyl) 6,7 dimethoxy 4(3H) quinazolinone which was prepared in the preceding Part C was used to prepare 2diethylamino-3-(o-tolyl)-6,7-dimethoxy-4(3H)-quinazolinethione by methods analogous to those used in Part D of Example III.

Part E-Preparation of 2-diethylamino-3-(o-tolyl)-6,7- dimethoxy 3,4 dihydroquinazoline.-The 2 diethylamino 3 (o tolyl) 6,7 dimethoxy 4(3H) quinazolinethione prepared in the preceding Part D was converted to Z-diethylamino 3 (o tolyl) 6,7 dimethoxy-3,4-dihydroquinazoline by the use of methods essentially analogous to those used in Part E of Example III.

pare the compounds listed in Table II below, starting with the appropriate quiuazolinone.

TABLE II N /Ri X i W N Y NH R2 tS-chloro I- H E-methoxy Benzo H -HsC-CH=CH -O-'GH2O- CH3 (GH2)2N(OHg)z -O-GH2-CHz-O H -(CH2) N H 5-methoxy -CH2OCH H i-Hz CH H .110 (CHz)4N" H aHl EXAMPLE VI (14.8 g.) of the previous step, in ml. of ethanol, was heated in a pressure bottle with 50 ml. of diethylamine at 150 C. for 24 hours. The solution was cooled, the liquids were evaporated, and the residue was triturated successively with water and ether. The remaining solid material (13.5 g.) was chromatographed on a column (325 x 50 mm.) of Florisil and a mixture of chloroform-benzene (1:1) eluted the desired material which was recrystallized from chloroform-isopropyl ether to give 4.95 g. of pure 2 diethylamino 3 (o-tolyl) 6,7 dimethoxy- 4(3H)-quinazolinone, M.P. 155158 0.; A 251; 293; 328 m (6 41,260; 13,400; 3,750).

Analysis.Calcd. for C H N O C, 63.33; H, 6.97; N, 13.85. Found: C, 63.51; H, 6.92; N, 13.79.

TABLE III 3 C1 N-Ra R1 R2 a on, -H2CCH=CH2 W H (3H3 H CHCH= CH3 E 3 H H CH3 CH3 C4H9 H H OCH:

H E MD Fs H a H3)=@ C1 H H H CHz- H l OCH;

1 0 EXAMPLE VII The procedures of Examples III and IV are used to prepare the compounds listed in Table IV, below, starting with the appropriate substituted o-aminobenzoic acid ester, isocyanate and amino compound.

To 5.0 grams of 2-dimethylaminoJ-methoxy-3,4-dihydroquinazoline was added ml. of 48 percent aqueous hydrobromic acid and the mixture was refluxed for 3 hours. The resultant solution was chilled and the precipitate was filtered and washed with ether, furnishing crystalline material Which was recrystallized from ethanolether to yield the desired product.

EXAMPLE IX Tablets.A tablet base is prepared by blending the following ingredients in the proportion by weight indicated:

Sucrose, U.S.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5

1 1 Into this tablet base there is blended sufficient 2-diethylamino-6,7-dimethoXy-3,4 dihydroquinazoline hydrochlo ride to provide tablets containing 0.1, 10 and 50 mg. of active ingredient per tablet.

EXAMPLE X Capsules-A blend is prepared containing the following ingredients:

Magnesium stcarate B 0.35

To this blend is added suificient 2-dimethylamino-6,7- dimethoxy-3,4-dihydroquinazoline hydrochloride to provide capsules containing 0.1, 10 and 50 mg. of active ingredient per capsule.

EXAMPLE XI Suspension.-A suspension of 2-dimethy1amino-6,7-dimethoxy'3,4-dihydroquinazoline is prepared with the following composition:

Elfective ingredient g 31.42 70% aqueous sorbitol g. 741.29 Glycen'ue, U.S.P ..g.. 185.35 Gum acacia (10% solution) ml v 100.0 Polyvinylpyrrolidone g 0.5

Distilled water, sufiicient to make 1 liter.

To this suspension, various sweeteners and flavorants may be added to improve the palatability of the suspension. The suspension contains approximately 25 mg. of effective agent per milliliter.

EXAMPLE XIII Sluti0n.A solution of Z-dimethylamino-6,7-dimethoxy-3,4-dihydroquinazoline is prepared with the following composition:

Etfective ingredient "grams" 30.22 Magnesium chloride hexahydrate do 12.36 Monoethanolarnine ml. 8.85 Proplyene glycol grams 37 6.0

Water, distilled 94.0

The resultant solution has a concentration of cfiective ingredient of 50 rug/ml. and is suitable for parenteral and especially for intramuscular administration.

EXAMPLE XIV Hypotensive activity was measured in hypertensive conscious dogs with systolic blood pressures of at least 160 mm. Hg. The hypertension was produced by the tech nique given by Goldblatt, H., Lynch, 1., Hansel, R. F. and Summerville, W. W., J. Exp. Med, 59, 347 (1934). Blood 12 pressure recordings were made according to the method of M. A. Prioli and M. M. Winbury, J. Appl. Physiol., 15, 323 (1960).

Oral doses of 20 mg./kg. of 2-dirnethy1amino-6,7-dimethoXy-3,4-dihydroquinazoline hydrochloride and 2-diethylarnino-6,7-dimethoXy-3,4-dihydroquinazoline hydrochloride vvere administered to hypertensive dogs. The blood pressure of the dogs so treated was lowered by approximately 25 mm. Hg by the administration of doses of each of the compounds, respectively.

What is claimed is:

1. A compound selected from the group consisting of those of the formulae and the mineral acid and organic acid addition salts thereof wherein X and Y are each selected from the group consisting of hydrogen, hydroxy, halogen, CF alkyl having up to 4 carbon atoms and alkoxy having up to 4 carbon atoms and X and Y, taken together, are benzo, methylenedioxy, and ethylenedioxy; R and R are each selected from the group consisting of hydrogen, alkyl having up to 6 carbon atoms, phenyl, naphthyl, su'bstituted phenyl wherein the substituent is halogen, CF alkyl having up to 3 carbons or alkoxy having up to 4 carbons, aralkyl compounds of the group phenylalkyl having up to 3 carbons in the alkyl moiety, trifluoromethylbenzyl, methoxybenzyl, tolylethyl and compounds wherein the carbon atom bearing the said aryl moiety is an optically active site, alkenyl and dialkylaminoalkyl having from 2 to 4 carbon atoms in the nitrOgen bridging alkyl moiety and up to 3 carbon atoms in the terminal alkyl moieties; R and R taken together, are cycloalkyl having from 3 to 7 carbon atoms; R is selected from the group consisting of hydrogen, alkyl having up to 4 carbon atoms, phenyl, naphthyl, substituted phenyl wherein the substituent is halogen, CF alkyl having up to 3 carbons or alkoxy having up to 4 carbons, phenylalkyl having up to 3 carbons in the alkyl moiety, triflnoromethylbenzyl, methoxybenzyl or tolylethyl; R is selected from the group consisting of morpholino, N-alkyl-piperazino with up to 6 carbon atoms in the alkyl moiety, N-alkenyl-piperazino, N- phenyl piperazino and substituted N-phenyl piperazino where the phenyl moiety is substituted with substituents selected from the group consisting of halogen, 01?}, alkyl having up to 6 carbon atoms and alkoxy having up to 6 carbon atoms; said alkenyl moieties in R R or R having up to 4 carbon atoms.

2. The compound of claim 1 where the compound is Z-diethylamino-3,4-dihydro-6,7-dimethoxyquinazoline.

3. The compound of claim 1 wherein the compound is Z-dimethylamino-3,4-dihydro-6,7-dimethoxyquinazoline.

References Cited Carrington: J. Chem. Soc., 1955, pp. 25278.

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner U.S. C1. X.R. 

